Research Area: The role of innate immunity mechanisms in development of type 1 diabetes

Type 1 diabetes (T1D) arises through autoimmune destruction of the insulin producing pancreatic β-cells and results in lifelong dependency on exogenous insulin injections, reduced quality of life, and increased risk for secondary complications. It is among the most common chronic childhood illness that in recent decades is being diagnosed at an earlier age with an increasing incidence in most developed countries.

Many inflammatory diseases, including T1D become evident only after tissue and organ damage have already progressed. In T1D, an estimated 80% of the beta cells have been destroyed at the time of diagnosis, and our studies show that autoimmunity has been occurring for years prior to clinical onset. This pre-clinical or pre-diagnosis time, during which there is progressive destruction of β-cells, offers a window for pre-onset interventions aimed at preserving islet function and delaying and/or preventing T1D. Relevant tissues such as pancreatic lymph nodes and islets are not accessible and we cannot reliably detect the dilute inflammatory molecules associated with T1D directly in the blood of pre and recent onset T1D patients. Sensitive methods that may allow for earlier prediction are needed.

Genomics technologies now offer unprecedented opportunities to fill the need for new biomarkers in T1D and other diseases. We have applied a novel bioassay to T1D, whereby the complex milieu of inflammatory mediators present in serum or plasma can be indirectly detected through their ability to drive gene transcription in peripheral blood mononuclear cells (PBMC) drawn from healthy, unrelated donors. Expressed genes are comprehensively measured with a genome-scale microarray. We have discovered that serum of recent-onset T1D patients induces a unique pro-inflammatory gene expression signature that includes numerous innate immunity genes and genes regulated, in part, by the inflammatory mediator interleukin-1 (IL-1). The signature is completely distinct from that induced by normal control sera. Importantly, the extracellular milieus associated with infectious or other autoimmune diseases drive distinct transcriptional signatures. Furthermore the T1D signature is evident >5 years prior to T1D onset and holds value in predicting onset in “at-risk” subjects as well as measuring the response of a patient to therapeutic intervention.

Our functional genomics and immunological studies of T1D also use the BioBreeding (BB) rat model of T1D. Evidence suggests that T1D initiating events occur at the β-cell level. There, perturbants, possibly infection or oxidative stress, promote apoptosis and/or cytokine production, which activates/recruits tissue-resident antigen (Ag) presenting cells to the islet, and ultimately the development of an adaptive immune response. Consistent with this working hypothesis, we have discovered that by 40 days of age, β-cells of all BB sub-strains express the chemokine eotaxin, and their islets exhibit pro-inflammatory expression profiles. This occurs before development of insulitis in spontaneously diabetic BBDR.lyp/lyp rats, thereby providing a mechanism for recruitment of immune cells to the islet. Direct expression profiling of immunocyte populations collected from pancreatic lymph nodes as well as serum signature studies of prediabetic BB rats has revealed a heightened innate immune state that begins shortly after weaning, well before evidence of adaptive T cell response. This innate state is driven, in part, by IL-1 and the actions of mast cells, as treatment of BB rats with either IL-1 receptor antagonist (IL-1RA) or mast cell inhibitors delays or prevents T1D onset.

Our efforts continue to better understand the events leading to T1D by employing genomics, histological, immunological, and bioinformatics tools and strategies to the analysis of T1D in humans and the BB rat. We have recognized the potential of a systems biology approach as well as its technical and analytical complexities. Therefore, our laboratory has focused on the development of a robust genomics infrastructure that is supported by more traditional, focused technologies and studies. The development of complex diseases like T1D involves the interplay of multiple genes, cell types and environmental factors. Thus, an integrated perspective of how these factors interact is vital towards the dissection and understanding of complex disease as well as a prerequisite for the development of successful treatment and prevention strategies. Our ongoing studies aim to define the nature of the innate immune processes that underlie T1D in humans and BB rats and how this may be modulated to prevent development of disease.